Objective
Type 1 diabetes occurs when the immune system attacks and destroys the beta cells within the pancreas that produce insulin. This leaves people with type 1 diabetes unable to regulate their own blood glucose, and they require lifelong treatment with multiple daily injections of insulin. In the past, scientists viewed these beta cells as passive victims of autoimmune attack. However, emerging evidence suggests that beta cells actively contribute through inflammatory signals that recruit and activate immune cells. One approved drug, teplizumab, delays type 1 diabetes by targeting immune cells, delaying the need for treatment with insulin by about 24 months. Learning more about how beta cells participate in this inflammatory process could inform better prevention strategies in the future.
Background Rationale
Prior research has shown that exposure to viruses is a risk factor for type 1 diabetes. One protein which might be involved in this process is called MDA5, which detects viral RNA and triggers production of inflammatory proteins called interferons. While this response normally fights viral infection, it may also drive immune-mediated destruction of beta cells. We already know that certain genetic mutations in MDA5 lead to increased risk of type 1 diabetes, and that the beta cells of people with newly-diagnosed type 1 diabetes have high levels of MDA5. Additionally, my work reveals that inflammatory stress in later phases of type 1 diabetes causes beta cells to degrade PD-L1, a critical surface protein that signals "self" to the immune system and protects beta cells from immune attack.
Description of Project
Objective
Type 1 diabetes occurs when the immune system attacks and destroys the beta cells within the pancreas that produce insulin. This leaves people with type 1 diabetes unable to regulate their own blood glucose, and they require lifelong treatment with multiple daily injections of insulin. In the past, scientists viewed these beta cells as passive victims of autoimmune attack. However, emerging evidence suggests that beta cells actively contribute through inflammatory signals that recruit and activate immune cells. One approved drug, teplizumab, delays type 1 diabetes by targeting immune cells, delaying the need for treatment with insulin by about 24 months. Learning more about how beta cells participate in this inflammatory process could inform better prevention strategies in the future.
Background/Rationale
Prior research has shown that exposure to viruses is a risk factor for type 1 diabetes. One protein which might be involved in this process is called MDA5, which detects viral RNA and triggers production of inflammatory proteins called interferons. While this response normally fights viral infection, it may also drive immune-mediated destruction of beta cells. We already know that certain genetic mutations in MDA5 lead to increased risk of type 1 diabetes, and that the beta cells of people with newly-diagnosed type 1 diabetes have high levels of MDA5. Additionally, my work reveals that inflammatory stress in later phases of type 1 diabetes causes beta cells to degrade PD-L1, a critical surface protein that signals "self" to the immune system and protects beta cells from immune attack.
Anticipated Outcome
In this project, I will examine whether MDA5 in pancreatic beta cells causes inflammatory signals leading to type 1 diabetes. Using mouse models of diabetes and human beta cells derived from induced pluripotent stem cells, I will determine how MDA5 changes how beta cells communicate with immune cells. Separately, to target later phases of type 1 diabetes, I will test whether a nanomedicine can target and destroy a protein called TRIM21 which degrades PD-L1. If effective, this would stabilize this protective immune checkpoint and potentially prevent diabetes.
Relevance to Type 1 Diabetes
These studies will reveal how beta cells participate in the inflammatory and autoimmune processes leading to type 1 diabetes. Rather than solely targeting immune hyperactivity, we can identify ways to protect beta cells directly, an approach that could complement immune-focused therapies to delay or prevent disease onset in high-risk individuals. Ultimately, this could spare patients from insulin dependence and its associated complications and costs.
Anticipated Outcome
In this project, I will examine whether MDA5 in pancreatic beta cells causes inflammatory signals leading to type 1 diabetes. Using mouse models of diabetes and human beta cells derived from induced pluripotent stem cells, I will determine how MDA5 changes how beta cells communicate with immune cells. Separately, to target later phases of type 1 diabetes, I will test whether a nanomedicine can target and destroy a protein called TRIM21 which degrades PD-L1. If effective, this would stabilize this protective immune checkpoint and potentially prevent diabetes.
Relevance to T1D
These studies will reveal how beta cells participate in the inflammatory and autoimmune processes leading to type 1 diabetes. Rather than solely targeting immune hyperactivity, we can identify ways to protect beta cells directly, an approach that could complement immune-focused therapies to delay or prevent disease onset in high-risk individuals. Ultimately, this could spare patients from insulin dependence and its associated complications and costs.